Penicillin is a group of antibiotics, which were among the first drugs to be effective against many previously serious diseases, such as bacterial infections caused by staphylococci and streptococci. All penicillins are β-lactam antibiotics and are used in the treatment of bacterial infections caused by susceptible, usually Gram-positive, organisms.
Penicillins are widely used today for administration by injection, typically by use of ready-to-use syringes pre-filled with an injectable suspension containing the active agent. However, pre-filled injectable formulations containing penicillins generally contain preservatives in order to provide the required stability and sterility even after long term storage of the product.
The United States Pharmacopeia (USP) states in “Penicillin G Benzathine Injectable Suspension” that penicillin G benzathine injectable suspension is a sterile suspension of penicillin G benzathine in water for injection with one or more suitable buffers, dispersants, preservatives, and suspending agents. Hence, the USP recommends the presence of preservatives in penicillin injectable compositions.
Typical preservatives for pharmaceutical use are parabens or formaldehyde. In particular, parabens are used primarily for their bactericidal and fungicidal properties in many applications, such as pharmaceutical compositions.
However, the presence of preservatives in a medicament can lead to serious health problems and side effects, in particular when administered to children. Moreover, parabens contain methanol, ethanol and propanol as side product, which further increase the risk for side effects upon administration of the medicament. In addition, injectable compositions are generally sterilized by autoclaving. However, when parabens are used as preservatives autoclaving may lead to the formation of toxic compounds such as methanol and propanol in the product.
Parabens are further becoming increasingly controversial, however, because they have been found in breast cancer tumors. Parabens have also displayed the ability to slightly mimic estrogen, a hormone known to play a role in the development of breast cancer. Another concern is that the estrogen-mimicking aspect of parabens may be a factor in the increasing prevalence of early puberty in girls. Further, parabens can cause skin irritation and contact dermatitis and rosacea in individuals with paraben allergies.
A commercially available injectable formulation is for example Polyflex®, which is an ampicillin injectable suspension for veterinary use containing per vial 90 mg methylparaben and 10 mg propylparaben as preservative.
Bicillin® L-A is a penicillin G benzathine injectable formulation, provided as ready-to-use disposable syringe containing 0.1% methylparaben, and 0.01% propylparaben.
Cilicaine® is a procaine penicillin injectable formulation, containing phenyl mercuric acetate as preservative.
U.S. Pat. No. 3,351,527 is directed to stabilized benzathine penicillin compositions, which include a minor amount of sodium formaldehyde sulfoxylate as preservative component.
GB 1151168 is directed to a stabilized therapeutic composition for parenteral administration comprising benzathine penicillin G (N,N′-dibenzylethylenediamine dipenicillin) in an aqueous suspending medium which includes a wetting agent for the crystals, polyvinylpyrrolidone, and sodium formaldehyde sulphoxylate.
As penicillin's are generally provided in the form of an injectable suspension, the drug's release and resulting plasma concentration largely depend on the time needed for the active particles to solubilize in the patient's body. Therefore, it is difficult with the formulations of the prior art to provide a constant drug release and to maintain a uniform plasma concentration.
Therefore, a need exists in the art for the provision of a ready-to-use penicillin injectable formulation, which is stable on storage, and which overcomes the problems of the prior art. In particular, it is aimed to provide a ready-to-use injectable suspension, which maintains stability and sterility even in the absence of any preservative. Furthermore, it is aimed to provide a ready-to-use penicillin injectable retard formulation for providing a prolonged and constant release of the active agent into the patient's body and to maintain a uniform plasma concentration.